KR100967889B1 - Antibacterial composition containing 2-iminobenzoimidazole derivatives - Google Patents

Abstract

The present invention relates to a fungicide composition comprising a 2-iminobenzoimidazole derivative represented by the following Chemical Formula 1 as an active ingredient, and the 2-iminobenzoimidazole derivative according to the present invention has a particularly excellent bactericidal effect against plant late blight. Do:

Formula 1

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ² is phenyl unsubstituted or substituted with one or more halogen atoms, aryl or aryloxy; Naphthyl; Phenoxymethyl unsubstituted or substituted with one or more halogen atoms, C _1-3 alkyl or C _1-3 alkoxy; Phenyl isoxazoles unsubstituted or substituted with one or more halogen atoms; Or 4-methyl-3-phenyl-1,2,4-oxadiazol-5 (4H) -one, unsubstituted or substituted with one halogen atom.

Description

Fungicide composition containing 2-iminobenzoimidazole derivatives {ANTIBACTERIAL COMPOSITION CONTAINING 2-IMINOBENZOIMIDAZOLE DERIVATIVES}

The present invention relates to a bactericidal composition comprising a 2-iminobenzoimidazole derivative, and more particularly to a bactericidal composition comprising a 2-iminobenzoimidazole derivative having an excellent bactericidal effect against plant late blight.

Among the harmful organisms in agrohorticulture, pathogens are most easily expressed when compared to pests and weeds, so the resistance of pathogens is serious when repeated use of conventional agricultural fungicides. Therefore, there is a need for the establishment of effective control technology through the development of agricultural fungicides having a new mechanism of action.

Phenamideamide fungicides, which are RNA biosynthesis inhibitors such as metalaxyl, oxadixyl, benalaxyl, and furalaxyl, developed in the early 80s, Although it showed an excellent control effect, resistance to it occurs soon and it is difficult to use.

Also, the sterol biosynthesis inhibitor (DMI), which was developed in the 80s and 90s, formed the mainstream of the fungicide market, flusilazole, fenarimol, nuarimol, and triforine. , Imazalil, triflumizole, bitertanol, triadimefon, hexaconazole, propiconazole, triadimenol, etc. Although it shows an excellent control effect against the fungal disease, the composition and cell organelles of the cell wall and taxonomically different from the other fungi had little control against the different pests and germs.

In addition, strobilurin-based fungicides, which have been developed since the late 90's, are an innovative fungicide that can control both fungi, late blight and fungal pathogens. Azoxystrobin, kresoxim-methyl, trifloxystrobin, pyraclostrobin and the like have been developed by Syngenta and Bayer et al. However, these strovirulin-based fungicides also have a much lower control effect against late blight and downy mildew than other pathogens. Therefore, in order to suppress the occurrence of drug-resistant bacteria, there is still a problem that must use a variety of drugs alternately.

An object of the present invention is to solve the above problems, to provide a bactericidal composition comprising a 2-iminobenzoimidazole derivative excellent in bactericidal effect against late blight.

In order to achieve the above object, the present invention provides a fungicide composition comprising a 2-iminobenzoimidazole derivative of the formula (1).

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ² is phenyl unsubstituted or substituted with one or more halogen atoms, aryl or aryloxy; Naphthyl; Phenoxymethyl unsubstituted or substituted with one or more halogen atoms, C _1-3 alkyl or C _1-3 alkoxy; Phenyl isoxazoles unsubstituted or substituted with one or more halogen atoms; Or 4-methyl-3-phenyl-1,2,4-oxadiazol-5 (4H) -one, unsubstituted or substituted with one halogen atom.

The bactericidal composition containing the 2-iminobenzoimidazole derivative according to the present invention has a very good bactericidal effect against plant late blight, especially tomato late blight.

The fungicide composition according to the present invention comprises a 2-iminobenzoimidazole derivative of formula (I):

[Formula 1]

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ² is phenyl unsubstituted or substituted with one or more halogen atoms, aryl or aryloxy; Naphthyl; Phenoxymethyl unsubstituted or substituted with one or more halogen atoms, C _1-3 alkyl or C _1-3 alkoxy; Phenyl isoxazoles unsubstituted or substituted with one or more halogen atoms; Or 4-methyl-3-phenyl-1,2,4-oxa diazol-5 (4H) -one, unsubstituted or substituted with one halogen atom.

In the compound of Formula 1, the preferred compound is

R ¹ is methyl; ethyl; profile; Heptyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Or benzyl unsubstituted or substituted with chloro or methyl;

R ² is unsubstituted or substituted by one or two bromo, chloro, aryl or aryloxy-substituted phenyl; Naphthyl; Phenylisoxazole, unsubstituted or substituted with methyl, methoxy or two chloro; Compound which is 4-methyl-3-phenyl-1,2,4-oxadiazol-5 (4H) -one substituted with one chloro.

Specific examples of the compound preferable as the benzothiazole derivative of Chemical Formula 1 are as follows.

1) 2- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) -1-phenylethanol

2) 1- (3,4-dichlorophenyl) -2- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) ethanol

3) 2- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) -1- (naphthalen-1-yl) ethanol

4) 1- (3,4-dichlorophenyl) -2- (1-ethyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) ethanol

5) 1- (3,4-dichlorophenyl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) ethanol

6) 2- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3,4-dichlorophenyl) ethanol

7) 2- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-bromophenyl) ethanol

8) 2- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-bromophenyl) ethanol

9) α- [1,1'-biphenyl] -4-yl-2,3-dihydro-2-imino-3- (2-propenyl) -1H-benzimidazole-1-ethanol

10) 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3,4-dichlorophenyl) ethanol

11) VII- (3,4-dichlorophenyl) -2,3-dihydro-2-imino-3-[(2-methylphenyl) methyl] -1H-benzimidazole-1-ethanol

12) α- (3,4-dichlorophenyl) -2,3-dihydro-2-imino-3-[(4-methylphenyl) methyl] -1H-benzimidazole-1-ethanol

13) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3,4-dichlorophenyl) ethanol

14) α- (3,4-dichlorophenyl) -3- [2- (diethylamino) ethyl] -2,3-dihydro-2-imino-1H-benzimidazole-1-ethanol

15) 1- (3,4-dichlorophenyl) -2- (1,2-dihydro-2-imino-1- (2-morpholinoethyl) benzo [d] imidazol-3-yl) ethanol

16) 1- (3,4-Dichlorophenyl) -2- (1-heptyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) ethanol

17) 1- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -3-phenoxypropan-2-ol

18) 1- (2,4-dichlorophenoxy) -3- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) propan-2-ol

19) 1- (2,4-dichlorophenoxy) -3- (1-ethyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propan-2-ol

20) 1- (4-methoxyphenoxy) -3- (1-ethyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propan-2-ol

21) 1- (p-tolyloxy) -3- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) propan-2-ol

22) 1- (4-methoxyphenoxy) -3- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) propan-2-ol

23) 1- (2,4-dichlorophenoxy) -3- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) propan-2-ol

24) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4-dichlorophenyl) ethanol

25) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-phenoxyphenyl) ethanol

26) 1- (2,4-dichlorophenoxy) -3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propane -2-ol

27) 1- (3,4-Dichlorophenoxy) -3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propane -2-ol

28) 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol

29) 1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl )ethanol

30) 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol

31) 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isoxazol-5-yl )ethanol

32) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl )ethanol

33) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isogen Sazol-5-yl) ethanol

34) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (3,4-dichlorophenyl ) Isoxazole-5-yl) ethanol

35) 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (2,4-dichlorophenyl ) Isoxazole-5-yl) ethanol

36) 4- (3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -2-hydroxypropyl) -3- ( 4-chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one

2-iminobenzoimidazole derivatives of the formula (1) used in the fungicide composition according to the present invention may be commercially available, or may be prepared by the method disclosed in WO 03/105779, for example By the reaction represented by Scheme 1, the compound of formula 1a can be obtained.

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ² is phenyl unsubstituted or substituted with one or more halogen atoms, aryl or aryloxy; Naphthyl; Phenoxymethyl unsubstituted or substituted with one or more halogen atoms, C _1-3 alkyl or C _1-3 alkoxy; Phenyl isoxazoles unsubstituted or substituted with one or more halogen atoms; Or 4-methyl-3-phenyl-1,2,4-oxadiazol-5 (4H) -one, unsubstituted or substituted with one halogen atom.

First, the starting material 2-aminobenzoimidazole (Compound 2 ) is dissolved in a solvent such as methyl ethyl ketone or acetone, acetonitrile, THF, toluene, and alkyl bromide (Compound 3 ) is added thereto. In this case, the compound 2 and the compound 3 may be used in a ratio of 1: 1 to 1: 5 equivalents, preferably 1: 1.25 equivalents. The mixture can then be refluxed for 4 hours and the product precipitated in salt form can be filtered to yield compound 4 . In this case, the starting material 2-aminobenzoimidazole (Compound 2 ) is commercially available or can be easily synthesized.

Subsequently, the obtained compound 4 and bromoacetyl compound 5 are dissolved in a solvent such as toluene in a ratio of 1: 1 to 1: 5 equivalents, preferably 1: 1.5, and refluxed for 4 hours to 1 day, or they are methylethylketone Alternatively, after dissolving in a solvent such as acetone, acetonitrile, THF, toluene and reacting at room temperature for one day, the precipitated product in the form of a salt may be filtered to obtain ketone compound 6 .

Subsequently, the obtained ketone compound 6 is dissolved in methanol, and a reducing agent such as sodium borohydride is added to 1 to 5 equivalents, preferably 3.5 equivalents, to the compound 6 , followed by reaction at room temperature for 4 hours to 1 day. 1a can be obtained.

In addition, in Chemical Formula 1, the compound of Chemical Formula 1b , in which R ² is unsubstituted or substituted phenoxymethyl, may be prepared by, for example, a method as shown in Scheme 2 below.

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

X is H or at least one halogen atom, C _1-3 alkyl or C _1-3 alkoxy, aryloxy.

Allyl-substituted ether compounds 8a can be obtained by refluxing phenol compound 7 with allyl bromide in the presence of a salt such as potassium carbonate in an organic solvent such as methyl ethyl ketone or acetone, acetonitrile, THF, toluene. In this case, the allyl bromide may be used in an amount of 1 to 5 equivalents, preferably 1.2 equivalents based on compound 7 . In addition, the starting material phenol compound 7 is commercially available or easily synthesized.

Subsequently, the obtained allyl phenyl ether compound 8a is dissolved in a solvent such as a mixed solution of dimethyl sulfoxide and distilled water (4: 1), and reacted with N-bromosuccinimide (NBS) at 0 ° C. to room temperature to give compound 9a. Can be obtained. In this case, the N-bromosuccinimide can be used in an amount of 1 to 5 equivalents, preferably 1.5 equivalents based on compound 8a .

Subsequently, a compound 1b can be obtained from 2-aminobenzoimidazole compound 4 in which compound 9a and R ¹ are substituted using a method similar to the reaction for obtaining compound 6 from compound 4 and compound 5 of Scheme 1. In this case, compound 4 may be used in the amount of 1 to 5 equivalents, preferably 1.5 equivalents based on compound 9a .

In addition, in Chemical Formula 1, the compound of Chemical Formula 1c , in which R ² is unsubstituted or substituted with one or more halogen atoms, may be prepared by, for example, a method as shown in Scheme 3 below.

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ⁴ is H or a phenyl group substituted with one or more halogen atoms.

Compound 13 can be obtained from isoxazole compound 12 in which compound 4 and R ⁴ are substituted using a method similar to the reaction for obtaining compound 6 from compound 4 and compound 5 of Scheme 1. In this case, compound 12 may be used in the amount of 1 to 5 equivalents, preferably 1.5 equivalents based on compound 4 . In addition, the starting material isoxazole compound 12 is commercially available or can be easily synthesized.

The obtained ketone compound 13 is dissolved in methanol, a reducing agent such as sodium borohydride is added, and then reacted at room temperature for 4 hours to 1 day to obtain compound 1c . In this case, the sodium borohydride may be used in the amount of 1 to 5 equivalents, preferably 3.5 equivalents based on compound 13 .

In addition, in Formula 1, the compound of Formula 1d wherein R ² is 3- (4-chlorophenyl) -4-methyl-1,2,4-oxadiazol-5 (4H) -one may be, for example, represented by Scheme 4 below. It can also be manufactured by the method.

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ⁴ is H or a phenyl group substituted with one or more halogen atoms.

First, dissolve the R ¹ is a substituted 2-amino-benzo imidazole (Compound 4) and R ¹ is a substituted oxadiazol jolon compound 9b in a solvent such as methyl ethyl ketone, acetone, acetonitrile, THF, toluene, dimethylformamide And reflux reaction. In this case, compound 9b can be used in 1 to 3 equivalents, preferably 1.5 equivalents based on compound 4 . In this case, 2-aminobenzoimidazole 4 substituted with R ¹ is commercially available or easily synthesized. The precipitate obtained can then be filtered to afford compound 1d .

The oxadiazolone compound 9b used in the reaction can be produced by the same method as in Scheme 5 below.

First, the oxime compound can be obtained by refluxing 4-chlorobenzonitrile (Compound 10 ) and hydroxylamine hydrochloride salt in a solvent such as methanol in the presence of a salt such as potassium carbonate. In this case, the hydroxylamine hydrochloride salt can be used in 1 to 5 equivalents, preferably 2 equivalents with respect to the compound 10 and potassium carbonate may be used in 1 to 5 equivalent, preferably 1.2 equivalent to the compound 10 . In addition, 4-chlorobenzonitrile (Compound 10 ) is commercially available or can be easily synthesized.

The oxime compound obtained can then be reacted with ethyl chloroformate at 0 ° C. to room temperature in the presence of a base such as triethylamine to afford 1,2,4-oxadiazol-5 (4H) -one compound 11 . . In this case, the triethylamine may be used as a 1 to 5 equivalent, preferably 1.2 equivalent based on that of Compound 10, ethyl chloroformate may be used in 1 to 5 equivalent, preferably 1.2 equivalent based on compound 10.

Subsequently, the obtained compound 11 can be reacted with allyl bromide in a solvent such as acetonitrile in the presence of KF and a catalytic amount of 18-crown-6 to give a compound 8b in which allyl is substituted. In this case, KF may be used in 1 to 10 equivalents, preferably 4 equivalents, based on compound 10 , and allyl bromide may be used in 1 to 5 equivalents, preferably 3 equivalents, based on compound 11 .

The allyl compound 8b obtained can then be reacted with N -bromosuccinimide at 0 ° C. to room temperature in a medium such as a mixed solution of dimethyl sulfoxide and distilled water (4: 1) to afford compound 9b . In this case, N-bromosuccinimide can be used in 1 to 5 equivalents, preferably 1.5 equivalents based on compound 10 .

Among the 2-aminobenzoimidazole derivatives of the general formula (1), the compounds of the general formulas ( 1c) and ( 1d ) are novel substances, and the present invention also provides these novel compounds.

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ⁴ is H, phenyl unsubstituted or substituted with one or more halogen atoms.

Where

R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl;

R ⁴ is H, phenyl unsubstituted or substituted with one or more halogen atoms.

2-iminobenzoimidazole derivatives of the formula (1) according to the present invention can be used as active ingredients of fungicide compositions against plant late blight.

The fungicide composition according to the present invention may include the 2-iminobenzoimidazole derivative of Formula 1 in an amount of 0.01 to 90% by weight.

In addition to the 2-iminobenzoimidazole derivative of Chemical Formula 1, the bactericide composition according to the present invention may further include, as an excipient, a suitable solid carrier, liquid carrier or other suitable adjuvant such as surfactant, adhesive, and the like. . That is, the fungicide composition may be used by formulating an agricultural composition by mixing the active ingredient with the excipient. As described above, the method of formulating the composition for farming may be any method generally used. At this time, solid carriers that can be used include talc, clay, bentonite, pyrophyllite, kaolin, diatomaceous earth, silica, etc., and liquid carriers include xylene, toluene, methylnaphthalene, N-alkylpyrrolidone, and the like. Nonionic surfactants (e.g., polyoxyethylene alkylphenylethers and polyoxyethylene fatty acid esters), anionic surfactants (e.g., alkylbenzenesulfonates, ligninsulfonates and dinaphthylmethanesulfonates) The adhesive may be polyvinyl alcohol, carboxymethyl cellulose, gum arabic, or the like.

In addition, the disinfectant composition containing 2-iminobenzoimidazole derivative of Formula 1 as an active ingredient is prepared from powder, hydrated powder, granule, emulsion concentrate, suspension solution, fumigant, gas, paste, etc. It can be used to sterilize agricultural products, seedlings, seeds and the like. For example, the 2-iminobenzoimidazole derivative of Chemical Formula 1 may be uniformly dissolved in hydrocarbon, acetone or alcohol with a suitable surfactant to prepare an emulsion concentrate or suspension solution. In addition, the 2-iminobenzoimidazole derivative of Chemical Formula 1 may be mixed with an inorganic powder and a suitable surfactant, and pulverized and homogenized to obtain a fine powder to prepare a hydrated powder. The composition thus prepared may be diluted with water of a desired concentration, mixed with an inorganic powder, and then mixed and mixed homogeneously and used as dust. In addition to the above composition may be combined with other agrochemicals such as insecticides, fungicides, herbicides, plant growth regulators or the like, or may be mixed with nutrients.

Hereinafter, the present invention will be described in detail through the following examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited by the following examples.

Example 1: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4- Dichlorophenyl Synthesis of Ethanol (Compound 24)

Step 1: Synthesis of 1- (4-chlorobenzyl) -1H-benzo [d] imidazol-2-amine

2-aminobenzoimidazole (0.27 g, 2.0 mmol, Aldrich) was dissolved in methyl ethyl ketone (10 mL), 4-chlorobenzyl bromide (0.51 g, 2.5 mmol) was added, followed by reflux reaction for 4 hours, and a salt. The precipitated product was obtained. The obtained product was filtered and washed with methylethylketone to give the title compound (0.44 g, 65%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.48 (d, 2H, J = 8.1 Hz), 7.31 (d, 2H, J = 8.1 Hz), 7.19-7.07 (m, 4H), 5.13 (s, 2H ), 4.45 (br s, 2H)

Step 2: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4-dichlorophenyl) ethane Synthesis of On

   1- (4-chlorobenzyl) -1H-benzo [d] imidazol-2-amine (0.26 g, 0.76 mmol) synthesized in step 1 was dissolved in 10 mL of toluene, and 2-bromo-2 ' , 4'-dichloroacetophenone (0.32 g, 1.2 mmol) was added, followed by refluxing for 4 hours. The product precipitated with salt was then filtered and washed with toluene and normal hexane to give the title compound (0.39 g, 95%).

¹ H-NMR (300 MHz, DMSO) δ 9.12 (br s, 1H), 8.21 (d, 1H, J = 8.5 Hz), 7.89 (d, 1H, J = 2.0 Hz), 7.76 (dd, 1H, J = 2.4 Hz, J = 8.5 Hz), 7.68-7.65 (m, 1H), 7.55-7.46 (m, 3H), 7.36-7.29 (m, 4H), 5.91 (s, 2H), 5.55 (s, 2H)

Step 3: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4-dichlorophenyl) ethanol Synthesis of

2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4-dichloro synthesized in step 2 above Phenyl) ethanone (0.44 g, 0.84 mmol) was dissolved in methanol (20 mL), sodium borohydride (0.11 g, 2.9 mmol) was added slowly, followed by stirring at room temperature for 4 hours. 10% hydrochloric acid solution was added thereto to terminate the reaction, and methanol was distilled off under reduced pressure. Ethyl acetate was added thereto and washed with distilled water. After drying over anhydrous magnesium sulfate, the solvent was evaporated to afford the title compound (0.37 g, 98%).

¹ H-NMR (300 MHz, DMSO) δ 9.22 (br s, 1H), 7.82 (d, 1H, J = 8.4 Hz), 7.59-7.25 (m, 10H), 6.26 (br s, 1H), 5.56 ( s, 2H), 5.32-5.29 (m, 1H), 4.53-4.35 (m, 2H)

Example 2: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4- Phenoxyphenyl Synthesis of Ethanol (Compound 25)

Step 1: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-phenoxyphenyl) ethanone synthesis

Same as step 2 of Example 1, except that 2-bromo-1- (4-phenoxyphenyl) ethanone was used instead of 2-bromo-2 ', 4'-dichloroacetophenone as starting material The method gave the title compound (76%).

¹ H-NMR (300 MHz, DMSO) δ 9.22 (br s, 1H), 8.12 (d, 1H, J = 8.8 Hz), 7.59-7.14 (m, 16H), 6.02 (s, 2H), 5.58 (s , 2H)

Step 2: Synthesis of 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-phenoxyphenyl) ethanol

2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4-dichlorophenyl) ethane as starting material 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-phenoxyphenyl) ethanone instead of one Except for the use, the title compound (88%) was obtained by the same method as Step 3 of Example 1.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.38 (d, 1H, J = 8.5 Hz), 7.31-6.65 (m, 17H), 5.79 (br s, 1H), 5.19-5.17 (m, 1H), 4.92 (s, 2 H), 4.25-4.11 (m, 2 H)

Example  3: 1- (2,4- Dichlorophenoxy ) -3- (1- (4- Chlorobenzyl ) -1,2- Dihydro -2- Minobenzo [d] imida Synthesis of zol-3-yl) propan-2-ol (Compound 26)

Step 1: Synthesis of 1- (allyloxy) -2,4-dichlorobenzene

To a solution of 2,4-dichlorophenol (16 g, 0.10 mol) in acetone (150 mL) was added K ₂ CO ₃ (17 g, 0.12 mol) and allyl bromide (10 mL, 0.12 mol). The reaction was refluxed for a time, and then cooled to room temperature. The solid component was then filtered off and the filtrate was distilled under reduced pressure and then separated by column chromatography (normal hexane) to give the title compound (20 g, 96%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.34 (d, 1H, J = 2.6 Hz), 7.13 (dd, 1H, J = 2.5 Hz, J = 8.8 Hz), 6.80 (d, 1H, J = 8.8 Hz), 6.07-5.98 (m, 1H), 5.47-5.28 (m, 1H), 4.57-4.55 (m, 2H)

Step 2: Synthesis of 1- (2,4-Dichlorophenoxy) -3-bromopropan-2-ol

1- (allyloxy) -2,4-dichlorobenzene (9.07 g, 44.7 mmol) synthesized in Step 1 was dissolved in a mixed solution (24 mL) of dimethyl sulfoxide and distilled water (4: 1), N -bromosuccinimide (8.7 g, 49 mmol) was slowly added while cooling with a cold water bath, followed by stirring at room temperature for 2 hours. Diethyl ether was added thereto and washed with distilled water and saturated aqueous sodium chloride solution. Then, dried over anhydrous magnesium sulfate, the solvent was evaporated and separated by column chromatography to give the title compound (11.9 g, 89%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.31 (d, 1H, J = 2.5 Hz), 7.14 (dd, 1H, J = 2.5 Hz, J = 8.8 Hz), 6.81 (d, 1H, J = 8.8 Hz), 4.38-4.23 (m, 3H), 4.09-4.02 (m, 2H), 3.01 (t, 1H, J = 6.5 Hz)

Step 3: 1- (2,4-Dichlorophenoxy) -3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) Synthesis of Propan-2-ol

Using 1- (2,4-dichlorophenoxy) -3-bromopropan-2-ol synthesized in Step 2 instead of 2-bromo-2 ', 4'-dichloroacetophenone as starting material Except for the title compound (74%) in the same manner as in Step 2 of Example 1.

¹ H-NMR (300 MHz, DMSO) δ 8.93 (br s, 1H), 7.62-7.23 (m, 11H), 5.68 (br s, 1H), 5.43 (s, 2H), 4.44-4.29 (m, 3H ), 4.18-4.06 (m, 2H)

Example 4: 1- (3,4-dichlorophenoxy) -3- (1- (4-chlorobenzyl) -1,2-dihydro-2- Minobenzo [d] imida Synthesis of zol-3-yl) propan-2-ol (Compound 27)

Except for using 3,4-dichlorophenol instead of 2,4-dichlorophenol as a starting material, 1- (allyloxy) -3,4-dichlorobenzene ( 74%) was prepared. Subsequently, the same method as in Step 2 of Example 3, except that 1- (allyloxy) -3,4-dichlorobenzene was used instead of 1- (allyloxy) -2,4-dichlorobenzene as the starting material. 1- (3,4-dichlorophenoxy) -3-bromopropan-2-ol (72%) was prepared. Then 1- (3,4-dichlorophenoxy) -3-bromopropan-2-ol instead of 1- (2,4-dichlorophenoxy) -3-bromopropan-2-ol as starting material Except for using, the title compound (76%) was obtained by the same method as Step 3 of Example 3.

¹ H-NMR (300 MHz, DMSO) δ 8.92 (br s, 1H), 7.65-7.23 (m, 11H), 5.62 (br s, 1H), 5.49 (s, 2H), 4.45-4.28 (m, 3H ), 4.19-4.07 (m, 2H)

Example 5: 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-fe Neil Eye Sergeant Zol-5-yl) ethanol (compound 28)

Step 1: Synthesis of 1-propyl-1H-benzo [d] imidazol-2-amine

The title compound (76%) was obtained in the same manner as Step 1 of Example 1, except that propyl bromide was used instead of 4-chlorobenzyl bromide as the starting material.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.44 (d, 1H, J = 7.5 Hz), 7.16-7.05 (m, 3H), 4.55 (br s, 2H), 3.89 (t, 2H, J = 7.5 Hz), 1.90-1.78 (m, 2H), 1.00 (t, 3H, J = 7.5 Hz)

Step 2: 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone synthesis

1-propyl-1H-benzo [d] imidazol-2-amine (100 mg, 0.57 mmol) and 2-bromo-1- (3-phenylisoxazol-5-yl) ethane synthesized in step 1 above One (0.15 g, 0.57 mmol, Aldrich) was dissolved in methylethylketone (4.0 mL) and stirred at room temperature for one day. To this, diethyl ether (40 mL) was added, sonicated, and the solid precipitated with salt was filtered and washed with diethyl ether to quantitatively obtain the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.94 (s, 2H), 8.18 (s, 1H), 8.05 to 8.02 (m, 2H), 7.7 (dt, J = 5.8, 6.4 Hz, 2H), 7.62 ~ 7.58 (m, 3H), 7.41-7.31 (m, 2H), 5.89 (s, 2H), 4.22 (t, J = 7.2 Hz, 2H), 1.78 (q, J = 7.3 Hz, 2H), 0.98- 0.88 (m, 3 H)

Step 3: Synthesis of 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol

2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) synthesized in step 2 above Ethanone (0.15 g, 0.42 mmol) was dissolved in 10 mL of methanol, sodium borohydride (47 mg, 1.3 mmol) was added and stirred at room temperature for one day. 1N HCl was added thereto to terminate the reaction, the solvent was distilled off under reduced pressure, dissolved in methylene chloride, and then washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. Then dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (70%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.71 (d, J = 1.3 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.42-7.37 (m, 3H), 7.08-6.89 (m , 4H), 6.67 (d, J = 0.9 Hz, 1H), 5.61 (s, 1H), 5.36-5.34 (m, 1H), 4.47 (t, J = 2.7 Hz, 2H), 3.83 (t, J = 7.2 Hz, 2H), 1.78 (q, J = 7.3 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H)

Example 6: 1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (1,2-dihydro-2-imino-1- Propylbenzo [d] imidazole 3-yl) ethanol synthesis (compound 29)

Step 1: 1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3- Synthesis of ethanone

2-bromo-1- (3- (4-chlorophenyl) isoxazol-5-yl) ethane instead of 2-bromo-1- (3-phenylisoxazol-5-yl) ethanone as starting material Except for using On, the title compound was obtained quantitatively in the same manner as in Step 2 of Example 5.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.93 (s, 2H), 8.20 (s, 1H), 8.07 (dd, J = 1.8, 6.7 Hz, 2H), 7.75-77.6 (m, 4H), 7.40 ~ 7.31 (m, 2H), 5.88 (s, 2H), 4.22 (t, J = 6.9 Hz, 2H), 1.77 (dd, J = 7.3, 14.5 Hz, 2H), 0.94 (q, J = 6.4 Hz, 3H)

Step 2: 1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3- Synthesis of Ethanol

Instead of 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone as starting material 1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazole synthesized in step 1 above The title compound (73%) was obtained by the same method as Step 3 of Example 5, except that 3-yl) ethanone was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.63 (t, J = 2.1 Hz, 2H), 7.37 ~ 7.34 (m, 2H), 7.06 ~ 6.91 (m, 3H), 6.85 ~ 6.80 (m, 1H) , 6.61 (d, J = 0.8 Hz, 1H), 6.21 (s, 1H), 5.32-5.28 (m, 1H), 4.43-4.30 (m, 2H), 3.68 (t, J = 7.2 Hz, 2H), 1.73 (dt, J = 7.3, 14.7 Hz, 2H), 0.91 (dt, J = 14.9 Hz, 3H)

Example 7: 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-fe Neil Eye Sergeant Zol-5-yl) ethanol synthesis (compound 30)

Step 1: Synthesis of 1-benzyl-1H-benzo [d] imidazol-2-amine

The title compound (84%) was obtained by the same method as Step 1 of Example 1, except that benzyl bromide was used instead of 4-chlorobenzyl bromide as starting material.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.47 (d, 1H, J = 7.5 Hz), 7.35-7.32 (m, 3H), 7.19-7.09 (m, 5H), 5.16 (s, 2H), 4.49 (br s, 2H)

Step 2: of 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone synthesis

Except that 1-benzyl-1H-benzo [d] imidazol-2-amine synthesized in Step 1 was used instead of 1-propyl-1H-benzo [d] imidazol-2-amine as starting material. The title compound was obtained quantitatively in the same manner as in Step 2 of Example 5.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.15 (s, 2H), 8.19 (d, J = 2.0 Hz, 1H), 8.04 (t, J = 2.0 Hz, 2H), 7.75-7.60 (m, 5H ), 7.52 (s, 2H), 7.42 to 7.17 (m, 6H), 5.91 (d, J = 16.6 Hz, 2H), 5.53 (d, J = 15.8 Hz, 2H)

Step 3: Synthesis of 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol

Instead of 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone as starting material 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) synthesized in step 2 above The title compound (80%) was obtained by the same method as Step 3 of Example 5, except that ethanone was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.43 ~ 7.38 (m, 3H), 7.28 ~ 7.24 (m, 4H), 7.16 (t, J = 3.7 Hz, 2H), 7.05 ~ 6.90 (m, 3H ), 6.76 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 0.9 Hz, 1H), 5.34-5.32 (m, 1H), 4.90 (s, 2H), 4.42-4.40 (m, 2H)

Example 8: 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-cle in Rophenyl) Isoxazole -5-yl) ethanol (compound 31)

Step 1: 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isoxazole-5- Synthesis of ethanone

2-bromo-1- (3- (4-chlorophenyl) isoxazol-5-yl) ethane instead of 2-bromo-1- (3-phenylisoxazol-5-yl) ethanone as starting material Except for using On, the title compound was obtained quantitatively in the same manner as in Step 2 of Example 5.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.14 (s, 2H), 8.21 (s, 1H), 8.07 (dd, J = 1.9, 6.7 Hz, 2H), 7.76 (dd, J = 3.0, 6.1 Hz , 1H), 7.69 (dd, J = 1.9, 6.7 Hz, 2H), 7.54 (dd, J = 3.0, 6.2 Hz, 1H), 7.45-7.32 (m, 8H), 5.93 (s, 2H), 5.56 ( s, 2H)

Step 2: 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isoxazole-5- Synthesis of Ethanol

1-benzyl-1H-benzo [d] imidazol-2-amine, instead of 1-propyl-1H-benzo [d] imidazol-2-amine, was used as a starting material, 2- (1,2-dihydro-2- 2- (1-benzyl-1, synthesized in step 1 above instead of imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone, Except that 2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isoxazol-5-yl) ethanone was used. In the same manner as in Step 3 of Example 5, the title compound (67%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ7.62 (d, J = 4.7 Hz, 2H), 7.37 (d, J = 4.7 Hz, 2H), 7.36 ~ 7.23 (m, 4H), 7.20 ~ 7.14 ( m, 2H), 7.07-6.63 (m, 3H), 6.81 (t, J = 6.0 Hz, 1H), 6.61 (d, J = 0.9 Hz, 1H), 6.04 (s, 2H), 5.32 (dd, J = 6.3, 9.9 Hz, 1H), 4.99 (s, 2H), 4.44 (t, J = 6.0 Hz, 2H)

Example 9: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- Phenylisoxazole -5-yl) ethanol (compound 32)

Step 1: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazole-5- Synthesis of ethanone

Example, except that 1- (4-chlorobenzyl) -1H-benzo [d] imidazol-2-amine was used instead of 1-propyl-1H-benzo [d] imidazol-2-amine as starting material The title compound was obtained quantitatively in the same manner as in step 2 of 5.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.21 (s, 2H), 8.03 (s, 1H), 7.81 to 7.72 (m, 2H), 7.62 to 7.60 (m, 1H), 7.57 to 7.33 (m, 11H), 5.96 (d, J = 10.4 Hz, 2H), 5.51 (d, J = 40.1 Hz, 2H)

Step 2: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazole-5- Synthesis of Ethanol

Instead of 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone as starting material 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazole synthesized in step 1 above The title compound (87%) was obtained by the same method as Step 3 of Example 5, except that -5-yl) ethanone was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.71 (d, J = 2.6 Hz, 1H), 7.69 (d, J = 3.4 Hz, 1H), 7.42-7.39 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 7.07-6.70 (m, 5H), 6.71 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 0.7 Hz, 1H), 5.32 (t, J = 3.9 Hz, 1H ), 4.86 (s, 2H), 4.39 (t, J = 2.6 Hz, 2H)

Example 10: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4- Chlorophenyl ) Isoxazole -5-yl) ethanol (compound 33)

Step B1: 2- (1- (4-Chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) eye Synthesis of Soxazol-5-yl) ethanone

2-bromo-1- (3- (4-chlorophenyl) isoxazol-5-yl) ethane instead of 2-bromo-1- (3-phenylisoxazol-5-yl) ethanone as starting material Except for using On, the title compound was obtained quantitatively in the same manner as in Step 2 of Example 5.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.21 (s, 1H), 8.23 (d, J = 3.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.79 to 7.56 (m, 1H ), 7.69 (d, J = 8.4 Hz, 2H), 7.56-7.27 (m, 8H), 5.95 (s, 2H), 5.59 (s, 1H)

Step 2: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) eye Synthesis of Soxazol-5-yl) ethanol

Instead of 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanone as starting material 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chloro synthesized in step 1 above) The title compound (72%) was obtained in the same manner as Step 3 of Example 5, except that phenyl) isoxazol-5-yl) ethanone was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.42 ~ 7.39 (m, 2H), 7.38 ~ 7.21 (m, 4H), 7.10 ~ 6.91 (m, 5H), 7.39 (d, J = 7.4 Hz, 1H) , 6.60 (d, J = 1.0 Hz, 1H), 5.33-5.29 (m, 1H), 4.89 (s, 2H), 4.46-4.35 (m, 2H)

Example 11: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (3,4- Dichlorophenyl ) Isoxazole -5-yl) ethanol (compound 34)

Step 1: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (3,4-dichloro Synthesis of Phenyl) isoxazol-5-yl) ethanone

1- (4-chlorobenzyl) -1H-benzo [d] imidazole-2 (3H) -imine (120 mg, 0.44 mmol) and 2-bromo-1- (3 synthesized in step 1 of Example 1 -(3,4-dichlorophenyl) isoxazol-5-yl) ethan-1-one (150 mg, 0.44 mmol) was dissolved in toluene (10 mL) and refluxed for one day. The product precipitated with salt was then filtered and washed with ethyl acetate to give the title compound (0.21 g, 91%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.33 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 8.06 (dd, J = 2.0, 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.76 (q, J = 3.0 Hz, 1H), 7.57-7.49 (m, 3H), 7.37 (q, J = 9.5 Hz, 4H), 5.92 (s, 2H), 5.57 (s , 2H)

Step 2: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (3,4-dichloro Synthesis of Phenyl) isoxazol-5-yl) ethanol

2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminoiminobenzo [d] imidazol-3-yl) -1- (3- (3, 4-dichlorophenyl) isoxazol-5-yl) ethanone (0.15 g, 0.30 mmol) is dissolved in methanol (5.0 mL), sodium borohydride (33 mg, 0.87 mmol) is added, and at room temperature for one day. Stirred. Subsequently, the solvent was distilled off under reduced pressure, and the product was dissolved in methylene chloride, and then washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. Then dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (0.12 g, 80%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.83 (d, J = 1.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.25 (d, J = 6.9 Hz, 1H), 7.11-6.14 (m , 5H), 6.76 (d, J = 7.5 Hz, 1H), 6.60 (s, 1H), 5.30 (s, 3H), 4.90 (s, 2H), 4.48 (d, J = 11.4 Hz, 2H)

Example 12: 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (2,4- Dichlorophenyl ) Isoxazole -5-yl) ethanol (compound 35)

2-bromo-1- (3- (2,4) instead of 2-bromo-1- (3- (3,4-dichlorophenyl) isoxazol-5-yl) ethan-1-one as starting material 2- (1- (4-chlorobenzyl) -1 quantitatively in the same manner as in Step 1 of Example 11, except that -dichlorophenyl) isoxazol-5-yl) ethan-1-one was used , 2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (2,4-dichlorophenyl) isoxazol-5-yl) ethanone was obtained, which obtained The title compound (50%) was obtained in the same manner as Step 2 of Example 11 as a starting material.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.30-7.72 (m, 3H), 7.11 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 1.1 Hz, 1H), 7.02-6.89 (m, 3H), 6.74 (d, J = 7.1 Hz, 1H), 6.67 (d, J = 0.7 Hz, 1H ), 5.35 (dt, J = 6.3, 7.3 Hz, 1H), 5.29 (s, 1H), 4.88 (s, 2H), 4.48 (dd, J = 2.2, 14.9 Hz, 2H), 4.37 (dd, J = 5.6, 14.9 Hz, 2H)

Example 13: 4- (3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -2- Hydroxypropyl ) -3- (4- Chlorophenyl ) -1,2,4- Oxadiazole Synthesis of -5 (4H) -one (Compound 36)

Step 1: Synthesis of 3- (4-chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one

Hydroxylamine hydrochloride salt (14 g, 0.20 mol) was dissolved in distilled water (50 mL) and potassium carbonate (14 g, 0.10 mol) was added. This solution was added slowly to a solution of 4-chlorobenzonitrile (14 g, 0.10 mol) in methanol (100 mL). After refluxing for 24 hours, the mixture was cooled to room temperature, methanol was distilled under reduced pressure, and extracted with ethyl acetate. Then, after drying over anhydrous magnesium sulfate, the solvent was evaporated to give an oxime product (25 g, 97%). The oxime product was dissolved in methylene chloride (200 mL), triethylamine (14 mL, 0.10 mol) was added while cooling in an ice bath, ethyl chloroformate (9.5 mL, 0.10 mol) was added slowly, and room temperature. Reaction was carried out for 4 hours. The reaction mixture was washed with distilled water, dried over anhydrous magnesium sulfate and the solvent was evaporated to give a solid product (25 g). To this product was added 5% sodium hydroxide solution (100 mL), refluxed for 6 hours, cooled and acidified with 35% HCl. The water layer of the product was extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (17 g, 88%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 11.52 (br s, 1 H), 7.68 (dd, 4H, J = 10.8 Hz, J = 74.3 Hz)

Step 2: Synthesis of 4-allyl-3- (4-chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one

3- (4-chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one (2.0 g, 10 mmol) synthesized in step 1 was dissolved in acetonitrile (50 mL), and KF (2.3 g, 40 mmol) and 18-crown-6 (catalyst amount) were added, followed by allyl bromide (2.6 mL, 30 mmol), followed by reflux for 24 hours to obtain the title compound (2.4 g, 93%). It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.59-7.51 (m, 4H), 5.92-5.79 (m, 1H), 5.33-5.14 (m, 2H), 4.29-4.26 (m, 2H)

Step 3: Synthesis of 4- (3-bromo-2-hydroxypropyl) -3- (4-chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one

4-allyl-3- (4-chlorophenyl) -1,2,4-oxadiazole-5 (4H) synthesized in Step 2 instead of 1- (allyloxy) -2,4-dichlorobenzene as starting material Except for using) -one, the title compound (74%) was obtained by the same method as Step 2 of Example 3.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.72-7.52 (m, 4H), 4.44-4.31 (m, 1H), 4.16-4.11 (m, 2H), 4.01-3.75 (m, 2H), 2.58 ( br s, 1H)

Step 4: 4- (3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -2-hydroxypropyl) -3- Synthesis of (4-chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one

4- (3-bromo-2-hydroxypropyl) -3- (4-chlorophenyl) -1 synthesized in Step 3 instead of 2-bromo-2 ', 4'-dichloroacetophenone as starting material The title compound (54%) was obtained by the same method as Step 2 of Example 1, except that 2,4-oxadiazol-5 (4H) -one was used.

¹ H-NMR (300 MHz, DMSO) δ 8.96 (br s, 1H), 7.80 (d, 1H, J = 8.4 Hz), 7.68 (d, 1H, J = 8.4 Hz), 7.48-7.09 (m, 10 ), 8.53 (br s, 1H), 5.48 (s, 2H), 4.35-4.18 (m, 2H), 4.09 (br s, 1H), 3.95-3.91 (m, 1H), 3.73-3.65 (m, 1H) )

The bactericidal activity against tomato late blight was examined using the following bioassay for the compounds prepared by the methods of Examples 1 to 13 and several commercially purchased compounds.

Synthesized or purchased compound of Formula 1 was dissolved in dimethyl sulfoxide, and Tween 20 solution was added to prepare a drug solution such that the final concentration of the drug was 100 ppm. At this time, the final concentrations of dimethyl sulfoxide and tween 20 were 1% and 250 ppm, respectively.

Active test

Phytophthora infestans PIT strain, a tomato late blight bacterium, was inoculated in oatmeal medium and cultured in an incubator at 20 ° C. to form a jujube sac. Spermatozoa was formed by adding sterile distilled water, and a spore suspension having a spore concentration of 5 × 10 ⁴ sporangia / mL was prepared.

The drug solution prepared in the 2-3 seedlings of tomato seedlings grown in the greenhouse for about 3 weeks was evenly sprayed on the plants, left indoors for 1 day, and then spray-inoculated with the distillate suspension inoculum. The tomato seedlings inoculated with the pathogen were treated in a humidified environment at 20 ° C. for 1 day, and developed for 2 days in a constant temperature and humidity room (20 ° C., 70 to 80% relative humidity), and then the lesion area ratio was examined.

For the results of the test, the control value was calculated according to Equation 1 below, and the results are shown in Table 1 below.

* The numbers in parentheses in the above table indicate the example numbers.

As shown in Table 1, it was confirmed that the 2-iminobenzoimidazole derivative compound has excellent bactericidal activity against tomato late blight.

Toxicity test

To determine the toxicity of the 2-iminobenzoimidazole derivatives, the microbial reversion mutant experiment, acute oral toxicity test on rats, and acute fish toxicity on Oryzias latipes with compounds 13 and 23 of Table 1 are as follows. The test was conducted.

(1) microbial return mutation experiment

For compounds 13 and 23 of Table 1, 4 of histidine-required strains TA100, TA1535, TA98 and TA1537 of Salmonella typhimurium to detect the presence of mutagenicity through microbial reverse mutation test Tests were performed using WP2uvrA, a strain of dogs and a tryptophan requirement strain of Escherichia coli.

The test material was treated by dissolving in DMSO, and concentration setting test was performed by diluting step to 1000, 500, 100 and 50 μg / plate with 5000 μg / plate as the highest concentration. Through this test, the application concentrations in this study were determined to be 25, 12.5, 6.25, 3.125, and 1.5625 μg / plate, and the metabolic activation method (S9-) and application (S9 +) tests were performed together with the negative and positive controls. It was.

As a result of the test, 5 strains of TA98, TA100, TA1535, TA1537 and WP2uvrA were used to increase colony production levels in each treatment group compared to the negative control in both direct method (S9-) and metabolic activation method (S9 +). It is not shown.

From the above results, it was confirmed that compounds 13 and 23 of Table 1 did not cause a reverse mutation (negative) for the strains used under this test condition.

(2) Acute Oral Toxicity Studies in Rats

Single dose (oral) toxicity tests for compounds 13 and 23 of Table 1 were performed using ICR mice. As a limit test, the oral dose of 2,000 mg / kg B.W. was administered once, followed by observation and investigation of the lethality, general poisoning symptoms, weight change, and autopsy findings for 2 weeks. The results were as follows.

end. No deaths were observed in all of the test groups in the first and second stages out of a total of six test groups (2,000 mg / kg), three in phase 1 and three in phase 2.

I. No abnormalities related to the test substance were observed in the test substance administration group (2,000 mg / kg).

All. Body weight measurements showed normal weight gain in all dose groups.

la. Autopsy findings of surviving animals revealed no unusual abnormalities.

From the above results, compounds 13 and 23 of Table 1 were classified into Globally Harmonized System (GHS) category 5 (Category 5) for chemical classification and labeling.

(3) Acute fish toxicity test on Oryzias latipes

Concentration tests were carried out in the acute fish toxicity test of compounds No. 13 and No. 23 of Oryzias latipes in Table 1, compound No. 13 was 0.50, 0.65, 0.85, 1.10 and 1.43 mg / L, compound No. 23 The respective concentrations were set at 0.50, 0.85, 1.45, 2.46 and 4.18 mg / L. The exposure method was exponential, the number of exposures per concentration was set to 10, and the exposure time was 96 hours.

As a result, LC ₅₀ (48 hours) of Compound 13 was 0.89 mg / L, and LC ₅₀ (48 hours) of Compound 23 was 2.09 mg / L, which was identified as 2nd and 3rd grade, respectively.

Claims (7)

A fungicide composition comprising a 2-iminobenzoimidazole derivative of formula 1 as an active ingredient: Formula 1

Where R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl; R ² is phenyl unsubstituted or substituted with one or more halogen atoms, aryl or aryloxy; Naphthyl; Phenoxymethyl unsubstituted or substituted with one or more halogen atoms, C _1-3 alkyl or C _1-3 alkoxy; Phenyl isoxazoles unsubstituted or substituted with one or more halogen atoms; Or 4-methyl-3-phenyl-1,2,4-oxadiazol-5 (4H) -one, unsubstituted or substituted with one halogen atom. The method of claim 1, R ¹ is methyl; ethyl; profile; Heptyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Or benzyl unsubstituted or substituted with chloro or methyl; R ² is unsubstituted or substituted by one or two bromo, chloro, aryl or aryloxy-substituted phenyl; Naphthyl; Phenylisoxazole, unsubstituted or substituted with methyl, methoxy or two chloro; Is 4-methyl-3-phenyl-1,2,4-oxadiazol-5 (4H) -one substituted with one chloro, Fungicide composition. The method of claim 1, A fungicide composition characterized in that the 2-iminobenzoimidazole derivative of Formula 1 is selected from the group consisting of: 2- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) -1-phenylethanol; 1- (3,4-dichlorophenyl) -2- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) ethanol; 2- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) -1- (naphthalen-1-yl) ethanol; 1- (3,4-dichlorophenyl) -2- (1-ethyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) ethanol; 1- (3,4-dichlorophenyl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) ethanol; 2- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3,4-dichlorophenyl) ethanol; 2- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-bromophenyl) ethanol; 2- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-bromophenyl) ethanol; α- [1,1′-biphenyl] -4-yl-2,3-dihydro-2-imino-3- (2-propenyl) -1H-benzimidazole-1-ethanol; 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3,4-dichlorophenyl) ethanol; α- (3,4-dichlorophenyl) -2,3-dihydro-2-imino-3-[(2-methylphenyl) methyl] -1H-benzimidazole-1-ethanol; α- (3,4-dichlorophenyl) -2,3-dihydro-2-imino-3-[(4-methylphenyl) methyl] -1H-benzimidazole-1-ethanol; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3,4-dichlorophenyl) ethanol; α- (3,4-dichlorophenyl) -3- [2- (diethylamino) ethyl] -2,3-dihydro-2-imino-1H-benzimidazole-1-ethanol; 1- (3,4-dichlorophenyl) -2- (1,2-dihydro-2-imino-1- (2-morpholinoethyl) benzo [d] imidazol-3-yl) ethanol; 1- (3,4-dichlorophenyl) -2- (1-heptyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) ethanol; 1- (1-allyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -3-phenoxypropan-2-ol; 1- (2,4-dichlorophenoxy) -3- (1,2-dihydro-2-imino-1-methylbenzo [d] imidazol-3-yl) propan-2-ol; 1- (2,4-dichlorophenoxy) -3- (1-ethyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propan-2-ol; 1- (4-methoxyphenoxy) -3- (1-ethyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propan-2-ol; 1- (p-tolyloxy) -3- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) propan-2-ol; 1- (4-methoxyphenoxy) -3- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) propan-2-ol; 1- (2,4-dichlorophenoxy) -3- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) propan-2-ol; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (2,4-dichlorophenyl) ethanol; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (4-phenoxyphenyl) ethanol; 1- (2,4-Dichlorophenoxy) -3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propane-2 -Ol; 1- (3,4-Dichlorophenoxy) -3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) propane-2 -Ol; 2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol; 1- (3- (4-chlorophenyl) isoxazol-5-yl) -2- (1,2-dihydro-2-imino-1-propylbenzo [d] imidazol-3-yl) ethanol ; 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol; 2- (1-benzyl-1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isoxazol-5-yl) ethanol ; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3-phenylisoxazol-5-yl) ethanol ; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (4-chlorophenyl) isoxazole- 5-yl) ethanol; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (3,4-dichlorophenyl) eye Soxazol-5-yl) ethanol; 2- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -1- (3- (2,4-dichlorophenyl) eye Soxazol-5-yl) ethanol; And 4- (3- (1- (4-chlorobenzyl) -1,2-dihydro-2-iminobenzo [d] imidazol-3-yl) -2-hydroxypropyl) -3- (4- Chlorophenyl) -1,2,4-oxadiazol-5 (4H) -one. The method of claim 1, A fungicide composition, characterized in that it is used for controlling plant blight. The method of claim 4, wherein A fungicide composition, characterized in that the plant blight is tomato blight. 2-iminobenzoimidazole derivatives of Formula 1c Formula 1c

Where R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl; R ⁴ is hydrogen, phenyl unsubstituted or substituted with one or more halogen atoms. 2-iminobenzoimidazole derivatives of Formula 1d: Formula 1d

Where R ¹ is C _1-7 alkyl; C _2-7 alkenyl; -CH ₂ CH ₂ NR ⁰ , wherein R ⁰ is diethyl or -CH ₂ CH ₂ OCH ₂ CH _2- ; Benzyl unsubstituted or substituted with one or more halogen or C _1-3 alkyl; R ⁴ is hydrogen, phenyl unsubstituted or substituted with one or more halogen atoms.